Abnormalities in Ca++ in the CSF have been observed in manic, depressed and schizophrenic patients. The present study explores the role of Ca++ channel blockers in schizophrenia. By employing a new sensitive method for the quantitation of verapamil and its two active metabolites, we have demonstrated for the first time the partitioning of verapamil and its metabolite into the CSF. By estimating the free fraction of the drug in plasma and employing correlation analysis for drug levels in CSF and plasma, we have found the drug transfer process across the ependymal surface to be diffusion controlled. In vitro binding, studies can approximate partitioning of verapamil into the CNS, and hence can provide a measure of correlating clinical outcome or other biochemical measures presently being investigated.